Inflammaging and Cardiovascular Disease

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Phytomedicine 23 (2016) 1119–1126

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Phytomedicine

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Inﬂammaging and cardiovascular disease: Management by medicinal plants

∗ Erfaneh Shayganni a, Mahmoud Bahmani b, Sedigheh Asgary c, Mahmoud Raﬁeian-Kopaei a,

a Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran

b Food and Beverages Safety Research Center, Urmia University of Medical Sciences, Urmia, Iran

c Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

a r t i c l e i n f o a b s t r a c t

Article history: Background: In aging, a host of molecular and cellular changes occur which accelerate alteration and progres- Received 23 August 2015 sion of inﬂammatory diseases. These conditions in the elderly people cause appearance of a phenomenon

Revised 6 November 2015 which has been denoted as “inflammaging”. Understanding the pathogenesis and finding new methods for Accepted 10 November 2015 management of inflammaging are essential. Purpose: In this paper we tried not only to explain inflammaging and its treatments with concentrating Keywords: on medical plants but to collect a sufficient collection of anti-inflammatory plants with focusing on their Aging mechanism of action.

Anti-inﬂammatory drugs Method: In this review paper, by searching in indexing cites, desired articles were obtained since 1995 by us-

Cardiovascular disease ing keywords of inflammation, inflammaging, inflammation pathophysiology, free radicals and inflammation, Inflammation aging inflammation, inflammatory disease, and plants or herbal medicine in inflammation. Inflammaging

Medicinal plants Sections: In advanced age the generation of free radicals increases in cardiovascular system. Pathological inflammation is also associated with production of excess free radicals More importantly, chronic inflammation makes aged people susceptible to age-related diseases. Some medicinal plants have been shown promising results in inhibition of inflammaging. Some other sections such as inflammation and inflammaging in cardiovascular diseases, oxidative stress in cardiovascular complications, prevention and treatment strategies are presented. Conclusion: The results of published papers show that the symptoms of several inflammatory diseases can be inhibited or treated by active ingredients from medicinal plants. © 2015 Elsevier GmbH. All rights reserved.

Introduction ( Nasri and rafieian-kopaei 2013; Rabiei et al. 2013a; Favarato et al. 2014 ). Aging is a phenomenon resulted from genetic, epigenetic The world’s population age is increasing and the aging popula- stochastic, and environmental events in different cells and tissues. tion is a risk factor for cardiovascular diseases (CVD). Aging generally In fact in aging, a host of molecular and cellular changes occur which causes some changes which, even in absence of usual risk factors, ren- accelerate these alterations and implicate in the progression of arte- der the cardiovascular system prone to some diseases ( Lakatta 20 0 0 ). rial diseases ( Rabiei et al. 2013b; Favarato et al. 2014 ). Pathological The progressive degeneration of the heart in elderly makes it inflammation is also associated with production of excess free radi- more vulnerable to stress and causes an increase in cardiovascu- cals arising predominantly from mitochondria ( Beller 2010; Rafieian- lar morbidity and mortality ( Brodsky et al. 2004 ). Cardiovascular kopaei et al. 2012 ). There are also evidences showing that in advanced diseases are also fuelled by some other risk factors such as di- age the generation of free radicals increase in cardiovascular system abetes ( Baradaran et al. 2013; Behradmanesh et al. 2013 ), hyper- ( Judge et al. 2005; Asadbeigi et al. 2014 ). More importantly, chronic tension ( Asgary et al. 2013; Ghorbani et al. 2013 ), and obesity inflammation makes aged people susceptible to age-related diseases ( Franceschi et al. 20 0 0 ). A wide variety of diseases including diabetes ( Asadbeigi et al.

Abbreviations: CVD, Cardiovascular diseases; NOS, Nitric oxide synthase; eNOS, En- 2014 ) cancer ( Azadmehr et al. 2011; Nasri and raﬁeian-kopaei 2014 ), dothelial nitric oxide synthase; LDLox, Oxidized low density lipoprotein; NSAIDs, Non-

steroidal anti-inflammatory drugs; DMARDs, Disease-modifying agents of rheumatoid infection (Bagheri 2013; Bagheri 2013), atherosclerosis (Rafieian- diseases; NF-k β, Nuclear factor- kb. Kopaei et al. 2011; Rafieian-Kopaei et al. 2014a ), cardiovascular dis- ∗ Corresponding author. Tel./fax: + 98 383 3330709. eases ( Khosravi-Boroujeni et al., 2013; Sarrafzadegan et al. 2013 ), E-mail address: rafi[email protected] (M. Rafieian-Kopaei). Alzheimer ( Rabiei et al. 2013c, 2014 ) and other degenerative diseases

( Mardani et al. 2014; Rafieian-Kopaei et al. 2014b ) are associated with metabolic syndrome are associated with coronary vasculopathy, and increased oxidative stress and inflammatory conditions and are de- with circulating serum factors which mediate the connections be- graded in aging. Moreover, the process of inflammation is involved tween these disease conditions. These circulating mediators are in initiation and development of a wide variety of chronic diseases mostly participated in systemic inflammation. Therefore, these fac- ( Paolisso et al. 1998 ). tors may show the evidence for their connections with cardiovascular In aging the normal balance between the oxidative stress and an- pathology ( Berg and Scherer 2005; Rafieian-Kopaei 2014 ). tioxidant system culminates in cardiovascular complications. These conditions in the elderly people cause appearance of a phenomenon Inflammaging and cardiovascular diseases which has been denoted as “inflammaging”. In fact, the word inflammaging is used to show inflammatory state in the aged individuals The association between systemic inflammation and increase in ( Franceschi et al. 20 0 0 ). the risk of cardiovascular diseases has stimulated basic and clini- Chronic inflammation in aging tissues “Inflammaging” is a perva- cal investigators to research for precise nature and the differences sive feature of aging and most age-related diseases are associated in the nature of traditional inflammation and inflammaging in rela- with inflammation. In fact inflammaging is described as systemic, tion to cardiovascular diseases. In this regard, although their different low-grade chronic inflammation in aged people, in absence of infec- roles in accelerating atherogenesis remain unresolved, however, it is tion. It is a great risk factor for mortality and morbidity in the elderly known that inflammatory response in elderly is not as fast as younger people ( Zhang et al. 2010 ). individuals. Inflammation can be beneficial facilitating the adapta- A mild inflammation is predictive of, and is associated with many tion, turnover and repair of many tissues. However, this inflammatory aging phenotypes. The etiology of inflammation in aging people and response might be impaired during aging which increase the suscep- its contribution in adverse health events is unknown. The pathways tibility to pathogens ( Griendling and FitzGerald 2003 ). that make us able to control inflammation are not fully established. More importantly, in aging period, a host of molecular and cellu- Hence, understanding the pathogenesis and finding new methods lar changes including genetic, epigenetic and environmental events for management of inflammation are beneficial. This paper, there- occur which increase the progression of arterial diseases. fore, aimed to present the recently published papers regarding in- In aged people, the tissues are mostly in a chronically inflamed flammation in cardiovascular diseases, focusing on the role of oxida- state, with no sign of infection. The generation of free radicals also tive stress. and to summarize the herbal medicines which have had increases, and makes aged people susceptible to cardiovascular dis- promising results in prevention and treatment of this phenomenon. eases ( Asadbeigi et al. 2014 ). Inflammaging is associated with increased levels of IL-1, IL-6, TNF Inflammation and cardiovascular disease and CRP which are independent risk factors for mortality and morbidity. In aging process interference occurs with anabolic signaling, Inflammation participates to the pathophysiology of a wide va- IL-6 and tumor necrosis factor-a increase, down-regulating insulin riety of chronic diseases particularly injury and infectious diseases. and insulin-like growth factor-1, as well as erythropoietin signaling Interaction of various cells in the adaptive and innate immune sys- and protein synthesis. Inflammaging can be due to the accumulation tems with inflammatory mediators modulates the acute and chronic of damaged macromolecules and cells which increases with age due inflammation causing various diseases. This coordination in inflam- to increased production and/or inadequate elimination. Inflammag- matory mechanisms triggers remodeling of the extracellular matrix, ing might also be due to increase in harmful agents produced by mi- oxidative stress, tissue injury, angiogenesis and fibrosis in various tis- croorganisms of the human body, including gut microbiota. In aging sues. These inflammatory mechanisms are involved in most of cardio- period, the gut microbiota may change and the capability of the gut vascular complications, including coronary artery disease, ischemia, to sequester these microbes and their products declines, leading to rheumatic disease, rheumatoid arthritis, plaque disruption, thrombo- chronic inflammation ( Pawelec, 1999 ). sis and atherosclerosis. The mastery of the inflammatory responses Increase in inflammation in aging also might be due to high necessitates the development of new approaches to the prevention level of cellular response to stress and damage (cellular senescence). and treatment of chronic diseases associated with aging, such as Senescent cells likely fuel age-related diseases such as cardiovascular atherosclerosis ( Libby, 2007 ). disease, because they secrete numerous proinflammatory cytokines, Although inflammation was previously considered as being a re- modifying the tissue microenvironment and altering the function of sponse to development of atheromatous vascular damage, it is now nearby normal cells. Immunosenescence also contributes to inflam- considered as the main causing factor in atherosclerosis rather than maging. In aging the adaptive immunity decreases and the innate im- being its result. In this regard, a dramatically increased risk of car- munity increases resulting in mild hyperactivity, which may lead to diovascular disease has been reported in patients with pre-existing local inflammatory reactions in elderly people. Coagulation is con- inflammatory diseases. Also, patients with autoimmune disorders in- sidered as a part of the inflammation system. Increase in activation of cluding lupus erythematous and rheumatoid arthritis have higher the coagulation system in age people also can increase the inflamma- rates of cardiovascular diseases such as atherosclerosis ( Franceschi tion. The higher incidence of thrombosis in the elderly has been at- et al. 20 0 0 ). Untreated infections such as periodontal disease which tributed to hypercoagulable state in elderly people ( Belge et al. 2002 ). cause inflammation are associated with increased risk of cardiovascular complications ( Candore et al. 2010 ). The inflammation mediators have been shown to participate in Oxidative stress in cardiovascular complications atheromatous changes and vascular insults. Secretion of a host of inflammatory factors might contribute to the increased cardiovascu- Reactive oxygen species induced oxidative stress play a cru- lar risks. The cardio-protective effects of many of drugs are mediated cial role in development of vasculopathies, such as hypertension, through improvement of systemic inflammation. The targeted sup- atherosclerosis and restenosis after angioplasty. Although atheroscle- pression of various pro-inflammatory cascades in adipocytes specifi- rosis was initially suggested to be the result of an injury to endothelial cally represents an exciting new therapeutic opportunity for the car- cells and subsequent macrophage infiltration, however, LDL oxidation diovascular disease area ( Berg and Scherer 2005 ). and its implication in formation of fatty streaks are very important in The mechanisms underlying cardiovascular complications by sys- process of atherogenesis ( Griendling and FitzGerald 2003 ). temic inflammation are not established. Type 2 diabetes melli- Various free radicals are produced in cardiovascular system and tus, hypercholesterolemia, atherosclerosis, hypercoagulability, and play a crucial role in vascular physiology as well as pathophysiology; E. Shayganni et al. / Phytomedicine 23 (2016) 1119–1126 1121

. − the most important of them are superoxide (O2 ), hydrogen perox- fruits with antioxidant activity, less or more, have suggested reduc- . − . ide (H2 O2 ), peroxynitrite (ONOO ) and nitric oxide (NO ). In vascu- tion in cardiovascular morbidity and mortality (Verlangieri et al. lature, superoxide reacts with nitric oxide to form the highly reac- 1985 ), particularly in regard to ischemic heart disease ( Gey and Puska tive molecule of peroxynitrite (ONOO.-) which has an important role 1989; Emmert and Kirchner 1999 ). in protein nitration and lipid peroxidation. One of the most impor- Some studies on combinations of antioxidant drugs and vitamins tant productions of lipid peroxidation is LDLox (Oxidized low density have also had positive results. Consumption of 800 IU/day vitamin E lipoprotein) which has crucial role in atherogenesis ( Madihi 2013a,b ). in patients with prevalent cardiovascular disease showed reduction Nitric oxide is produced normally by endothelial nitric oxide syn- in the myocardial infarction ( Boaz et al. 20 0 0 ). thase (eNOS), but in process of inflammation, inducible NOS can also In another study in India, combined consumption of vitamins A, C, be expressed in smooth muscle cells and macrophages ( Asgary et al. E, and beta-carotene were protective against oxidative stress and car- 2014 ). diac necrosis. They also were useful in reduction of the cardiac events Nitric oxide plays an important role in platelet aggregation. Nitric and in preventing complications ( Singh et al. 1996 ). oxide which is an important mediator of endothelium-dependent va- Combined supplementation with vitamins C and E reduced the sodilation also has a crucial role in maintaining smooth muscle cell progression of carotid atherosclerosis ( Salonen et al. 20 0 0 ). Probucol growth and function ( Rafieian-Kopaei et al. 2014c ). alone or in combination with antioxidant vitamins seems to be ef- The function of most of free radicals including superoxide and fective in reduction of subsequent restenosis rates ( Tardif et al. 1997; hydrogen peroxide on cardiovascular system is critically dependent Yokoi et al. 1997 ). on the amounts produced ( Rafieian-Kopaei et al. 2013; Nasri and Most of the above mentioned studies are modest in size and in- Rafieian-Kopaei 2014 ). In low concentrations, they modulate the volved subgroups where more than one antioxidant (combinations function of biochemical pathways mediating the responses such therapy) was used. However, in large randomized clinical trials the as growth of vascular smooth muscle cells ( Rafieian-Kopaei et al. results were not all consistent with results of the above mentioned 2013; Rafieian-Kopae et al. 2014d ) . However, in high concentra- studies. Pooled data from over 77,0 0 0 subjects and randomized trials tions, free radicals can cause DNA damage and apoptosis as demon- of vitamin E as well as 6 trials of ß- carotene with over 131,0 0 0 partic- strated in smooth muscle and endothelial cells ( Rafieian-Kopaei ipants revealed that the vitamin E was not effective and ß-carotene 2014; Baradaran et al. 2014 ). Pathological inflammation is generally consumption was associated with a worse outcome ( P = 0 . 003). associated with excess free radicals and in advanced age the gener- A large, long-term trial, on women at high risk for cardiovascu- ation of free radicals increases, especially in cardiovascular system. lar diseases reported that vitamin C, vitamin E or ß carotene had no More importantly, chronic inflammation makes aged people suscep- significant effect on cardiovascular events ( Cook et al. 2007 ). Another tible to age-related diseases, including cardiovascular complications large trial in Cambridge on the effects of vitamin C or vitamin E also ( Franceschi et al. 20 0 0 ). revealed no significant reduction on the risk of major cardiovascular events ( Sesso et al. 2008 ) . Although the statistical analyses have Prevention and treatment strategies suggested overall significance of antioxidant therapy in some studies, only those trials using probucol with or without antioxidant vitamins Anti-inflammatory drugs showed significant effect ( Tardif et al. 1997 ). N-Acetylcysteine, in a trial on acute coronary syndrome, also produced significant improve- When the inflammatory response is no longer needed, it should ment in cardiac index in patients treated with streptokinase ( Arstall be terminated to prevent unnecessary bystander damage to tis- et al. 1995 ). sues. The most important anti-inflammatory drugs include non- Hence, there it is necessary to search for more scientific evidence steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and of the relative contribution of antioxidant constituents in inhibition disease-modifying agents of rheumatoid diseases (DMARDs) ( Singh and progression of cardiovascular events ( Badimon et al. 2010 ). 2012 ). NSAIDs and glucocorticoids are used in order to relieve symptoms, while, DMARDs are used with the aim of reducing or prevent- Anti-inflammatory plants ing tissue damage which are caused by inflammatory attack. Unfor- tunately, all of these have unacceptable side effects. Moreover, it is Targeting the desired pathway through treating inflammation is necessary to find out drugs for very long period of times in order not easy because of a wide range of changes in pathology as a conse- to design a successful anti-inflammatory therapy for chronic disease. quence of existence of many inflammatory mediators and pathways However, more potent anti-inflammatory therapy, usually has greater in inflammation ( Qiuhong et al. 2013 ). chance for adverse effects to host defense. For example, increased risk Cyclooxygenase and lipoxygenase pathways and possibly some for infections are more observed in patients taking anti-TNF α therapy other mechanisms of initiation of inflammation can be efficiently ( Tabas et al. 2013 ). Nowadays, more attention has been paid to medic- stopped by some of the phytochemicals found in certain plants as inal plants with antioxidant activity. well as aspirin ( Lavet et al. 2013 ). NSAIDs and corticosteroids have an extensive use in the current treatment of inflammatory disor- Potential role of antioxidants ders in Western medicine. Lately, phytochemicals and their anti- inflammatory efficacies have attracted more attention in treatment Although free radicals are able to damage cells or its components of inflammation. Therefore; we tried to list and introduce some of by oxidizing proteins or DNA or causing lipid peroxidation, but they these kinds of herbal drugs in this study ( Xu et al. 2007 ). also possess crucial useful physiological functions. The useful func- Symptoms of several inflammatory diseases can be inhibited by tion of antioxidant systems should not be removal of free radicals en- Chinese Material Medica, such as Qijie Granule including the root tirely, but instead keeping oxidative stress at a level below which they of Astragalus membranaceus, the resin of Dranaena cochinchinensis would trigger the inflammatory cascade, a series of intra-nuclear and (Lour.) S.C. Chen, the root of Angelica sinensis (Oliv.), Diels, the dried intra-cellular signaling which results in the release of destructive in- twig of Cinnamomum cassia Presl ( Zhang et al. 2004 ), the dried rattan flammatory cytokines ( Valko et al. 2007 ). of Sargentodoxa cuneata (Oliv.) Rehd. etwils, the root of Rheum pal- Progress has been made regarding the role of the signaling cas- matum L., the resin of Commiphora myrrha Engl., the root of Paeonia cades in inflammatory process and early studies have also suggested lactiflora Pall., and the root of Glycyrrhiza uralensis Fisch, which are that antioxidants might be useful in the treatment of vascular dis- proven to have acceptable curative effects in treating chronic pelvic eases ( Hall Ratclife 1949 ). Studies on the effects of vegetables and inflammation through improving the blood viscosity and regulating 1122 E. Shayganni et al. / Phytomedicine 23 (2016) 1119–1126

Table 1 Anti-inﬂammatory compounds of plant origin.

Compounds Uses Mechanism of action reference

Seeds of Phaseolus angularis Wight Anti-inflammation Dercreases NO, PGE2, iNOS, COX2, (Yu et al. 2011) NF- κβ Bark of Cinnamomum cassia Blume " Decreases NO iNOS, COX2 , NF- κβ (Yu et al. 2012) Dried roots Asparagus cochinchinensis " Decreases MPO (Lee et al. 2009) Merrill Aerial of Houttuynia cordata Thunb " Decreases NO, COX2 (Li et al. 2011c) Roots of Scutellaria baicalensis Georgi " Decreases IL2, IL6, IL12, IL1 β, TNF- α, (Kim et al. 2009a) NF- κβ, I κβ Aerial part of Andrographis paniculata " Decreases IL6, COX2, IL1 β, TNF- α (Parichatikanond et al. 2010) The fruits of Forsythia koreana Nakai " Decreases NO, iNOS, COX-2 (Lim et al. 2008) Dried heart wood of Caesalpinia sappan L. " Decreases NO, PGE2, iNOS, COX2 , IL-6 , (Wang et al. 2011) IL1 β, TNF- α, and increases IL10 Corolla of Carthamus tinctorius L. " Decreases NO,PGE2,iNOS, COX2 , NO, (Jun et al. 2011) iNOS TNF- α, NF- κβ Inflorescence of Chrysanthemum indicum " Decreases NO,PGE2,iNOS, COX2 (Wu et al. 2011c) Linne Ripe fruit of Evodia rutaecarpa " Decreases NO, iNOS (Ko et al. 2007) Roots of Glycyrrhiza uralensis Fisch. " Decreases NO, iNOS,IL-6, NO, NF- κβ, (Yu et al. 2012) IL1 β, I κβ Roots of Polygala tenuifolia Willd. " Decreases NO, PGE2, iNOS, COX2 , IL1 β, (Cheng et al. 2005) TNF- α Dried bark of Phellodendron chinense " Decreases COX-2, IL-6 (Xian et al. 2011) Schneid. Fruit of Vitex trifolia L. " Decreases iNOS, IL-6, IL-1 β, TNF- α and (Matsui et al. 2009) increases IL-10 Pericarp of Zanthoxylum schinifolium Sieb. " Decreases IL-8, TNF- α, NF- κβ, I κβ (Cheong et al. 2011) et Zucc Roots of Angelica sinensis (Oliv.) Diels " Decreases iNOS, COX-2, IL1 β, TNF- α (Cao et al. 2009) Roots of Clematis chinensis Osbeck " Decreases COX-2, IL1 β, TNF- α, NF- κβ (Peng et al. 2011) Leaves of Plectranthus amboinicus (Lour.) " Decreases COX-2, TNF- α, NF- κβ, I κβ (Deng et al. 2011) Spreng Branches and leaves of Taxillus " Decreases NO, iNOS, COX-2, TNF- α (Deng et al. 2011) liquidambaricola Hosokawa Aerial part of Pogostemon cablin (Blanco) " Decreases, IL1 β, TNF α, NO, PGE2, (Li et al. 2011) Benth iNOS, COX2, NF- κβ Young shoot of Aralia elata Seemann " Decreases IL1 β, TNF α, NO, PGE2, (Suh et al. 2007) NF- κβ, I κβ Flower of Glossogyne tenuifolia Cass " Decreases PGE2, iNOS, COX-2, IL-6, (Wu et al. 2004) IL-12, IL1 β, TNF- α, NF- κβ Dried roots of Alpinia conchigera Griff " Decreases NO, iNOS, IL1 β, TNF- α, (Lee et al. 2006) NF- κβ Roots of Sophora alopecuroides L. " Decreases IL-6, IL1 β (Wang et al. 2012c) Leaves of Cistus Lourifolius Linn. (Cistaceae) Inflammatory ailments such Inhibits activity of IL-1 α and PGs (Kupeli and Yesilada 2007) as rheumatism and renal inflammation Roots of Daphne pontica Linn. Anti-tumor Inhibits production of PGE2 and IL-1 β (Kupeli and Yesilada 2007) (Thymelaeceae) Fruit rinds of Garcinia mangostana Linn. Treatment of trauma and Block production of iNOS and COX-2 (Chen et al. 2008) (Guttiferas; Clusiaceae) skin infections Fruit of Gardenia jasminoides Ellis Treatment of inflammation Block production of COX-2, NF- κβ (Koo et al. 2006) (Rubiaceae) and I κβ Leaves of Piper ovatum Vahl (Piperaceae) Treatment of inflammation Inhibitory effecr on production of (Siva et al. 2008) COX-1 Hydroethanolic (70%) extract of " Decreases IL-1 β, IL-10 and NO release, (Alberto et al. 2009) Macrosiphonia longiflora and possibly the PGs. B. incarum, Baccharis boliviensis , Ch. " Inhibit COX-1 and COX-2 activities ( Calle et al. 2012 ) atacamensis and P. lucida ethanolic extracts J. seriphioides and P. lepidophylla extracts " Effect on COX-2 activity but not on the (Torres Carro et al. 2007) enzyme expression, Essential oil of Eugenia caryophyllata Nasal obstruction, Inhibitory effect musculoskeletal pain, inflammation on COX-2 activity (Ozturk and Ozbek 2005) Ethanol extracted of Desmodium Injuries Inhibition of prostoglandin synthesis (Shirani et al. 2011) pauciflorum, Mangifera indica and Andrographis paniculata Curcumin (a naturally-occuring yellow Atherosclerosis, Alzheimer ´s Inhibition of lipooxigenase and COX-2 (Song et al. 2001) pigment present in the rhizomes of the disease, Arthrits and plant curcuma Longa L. (Zingiberaceae)) Pancreases Resveratol (phytoalexin polyphenol) Anticarcinogenic and Inhibition of COX-1 and COX-2 (Jangand Pezzutto 1999) present in grape skin, red wines and anti-platelet activity other plants Flavonoids baicalein (isolated from roots of Anticancer agent Inhibition of 5-LO and LTC4 and PGE2 (Middelton et al. 20 0 0) scutellaria baicalensis Georgi (Lamiaceae) ( continued on next page ) E. Shayganni et al. / Phytomedicine 23 (2016) 1119–1126 1123

Table 1 ( continued )

Compounds Uses Mechanism of action reference

Cirsilio (isolated from achillea Leuchemia Inhibits production of COX-2 activity (Lindolfi et al. 1984) fragrantissima Forssk (Asteraceae)), Luteolin, morin Chrysin, apigenin and pheloretin Anti-inflammatory activity Inhibits COX-2 expression and platelet (Raso et al. 2001) aggregation Silbin, silydian and silychristin, ( from Anti-inflammatory activity Inhibit both LO and COX activity (Gupta et al. 20 0 0) silybum marianum L. (Milk thistle) (Asteraceae) Biflavon(from ginkgo biloba L. Arthtitic inflammation Inhibit PLA2 (Kim et al. 1999) ( ginkgoaceae) Tectorigenin and tectoridin (isolated from Anti-inflammatory activity Inhibits production of COX-2 (Yamki et al. 2002) rhizomes of belomcanda chinensis L . (Iridaceae)) Platycodin D (isolated from roots of “ Inhibits production of COX-2 (Kim et al. 2001) platycodon grandiflorum A. (campanulaceae) Ursolic acid and oleanic acid isomers “ Inhibit production of COX-2 (Suh et al. 1998) (extracted from plantago major L. (plantaginaceae) B-tumerone and artumeron (sesquiterpens Respiratory problems Inhibit LPS-induced PGE2 production (Hong et al. 2002) from Curcuma zedoaria L. (Zingiberaceae) Fatty acids extracted from Plantago major Anti-inflammatory activity Inhibit both COX-A and COX-2 (Ringbom et al. 2001) L. (Plantaginaceae) CAPE (Caffeic acid phenetyl ester, a Anti –inflammatory, Inhibits both COX-A and COX-2 (Michaluat et al. 1999) cpumpond produced by honeybees from anticarcinogenic, the gum of various plants) anti-mitogenic and immunomedulator Quinazolinocarboline alkaloid rutacarpine Antithrombotic effect Inhibit LPS-induced PGE2 production, (Woo et al. 2001) (from Evodia rutaecarpa Bentham inhibition of TXA2 (Rutaceae)) Aqueous and alcholic extract of Achillea Treatment of gastro- Inhibition of arachidonic acid (Benedik et al. 2007) millefolium Linn . (Asteraceae) intestinal andhepato-biliary disorders, skin inflammasion Aspilia africina (Pars.) (Asteraceae) Stops blood flow from fresh Inhibit action of mediators like (Okoli et al. 2007) wounds, traditional histamine, 5-HT, kinins and treatment of malaria prostanoieds Ethanolic extract of Bacopa monnieri Treatment of bronchitis, Suppres PGE1, bradykinin and (Channa et al. 2006) (Linn.) penn (scrophulariacceae) asthma and rhumatism serotonin Chloroform extract of Bryonopsis Laciniosa Anti-inflammatory activity Inhibits increasing of fibroblasts and (Gupta et al. 2003) (Linn.) (Cucurbitaceae) in chronic and acute synthesis of mucopolysacharids disease during formation of granuloma Neptin (isolated from dichloromethane Hepatoprotective and Inhibits NF- κβ activity (Okoli et al. 2007) extract of arial parts of Eupatorium against fever and arnottianum Grieseb. (Asteraceae) rheumatism

T-lymphocytic sub groups ( Zhao et al. 2010 ). Contrasting with west- dation by oral delivery. Hence, it seems that it is essential to set ern drugs; boiling, steaming, treating with salt or vinegar, frying, or up the smallest effective parts of the structure and a useful form charring as some specific treatments are subjecting before use of of direction for anti-inflammatory polysaccharides in further studies these plants in decoctions or in the manufacture of herbal products ( Mendes et al. 2012 ). ( Aggarwal and Shishodia 2006 ). It has been reported that essential oils of some medicinal plants It has been shown that active ingredients from medicinal plants have significant anti-inflammatory activities ( Dunga et al. 2009 ). For play a significant part in the prevention and treatment of inflam- example, secretion of pro-inflammatory cytokines such as TNF- α, IL- matory diseases ( Schepetkin and Quinn 2006 ). A characteristic of 1 β, and NF- κβ in RAW264.7 cells, a mouse macrophage-like cell line, medicinal plants is their unique structural diversity and wide-ranging that are induced by lipopolysaccharide (LPS) can be obviously pre- of pharmacological effects in contrast with common synthetic anti- vented by applying the essential oil of the buds of Cleistocalyx op- inflammatory drugs ( Qiuhong et al. 2013 ). erculatus (Roxb.) Merret Perry. Additionally, this oil can suppress the Recently, polysaccharides, which are widely used in the biomed- nuclear translocation of the p65 subunit and has the ability of inhibit- ical field as a result of their therapeutic effects and relatively low ing a phorbolester- induced which caused ear swelling and the water toxicity ( He et al. 2012 ), are screened for their anti-inflammatory content of the skin in BALB/c mice ( Lin et al. 1997 ). All together, these activities based on their unique structures in herbal plants. For ex- results suggest the anti-inflammatory effect of these essential oil example, it has been revealed that the main component of Astragalus tracts by suppressing the expression of pro-inflammatory cytokines. membranaceus Bunge and Astragalus polysaccharides, have anti- It is proven that alkaloids are the main bioactive components in inflammatory ability involving the inhibition of TNF- α and IL-1 β and anti-inflammatory treatments, such as matrine. Matrine is extracted reduction of nuclear factor- kb (NF-k β) activity ( Quang et al. 2012 ). from the root of Sophora flavescens Ait, in order to use in treat- The challenging part of using the polysaccharide drugs is the diffi- ment of some inflammatory diseases, such as enteritis, hepatitis and culty of targeting a specific location not only because of their large atopic dermatitis by inhibiting the activation of inflammatory signal molecular weight but also due to their easy digestion and oral degra- and also, expression of pro-inflammatory mediators in human skin 1124 E. Shayganni et al. / Phytomedicine 23 (2016) 1119–1126 keratinocytes, fibroblasts, Kupffer cells, and rat intestinal micro- ficiently used is extracting or isolating components from medical vascular endothelial cells ( Liu et al. 2007; Zhang et al. 2008; Cheng plants in order to develop anti-inflammatory drugs. It should be note et al. 2009; Zhang et al. 2011 ). Moreover, it has been found that that the pathological inflammation is associated with production of the alkaloid, matrine, can reduce the increased levels of TNF- α, IL- excess free radicals and medicinal plants mostly counteract oxidative 6 and HMG β1 induced by LPS, in both in vivo and in vitro situations stress by reducing free radicals ( Asadi-Samani et al. 2014; Bahmani ( Havsteen 1983 ) (see the table). et al. 2014 ). Therefore, isolation of anti-inflammatory compounds Citrus fruits, tea and wine are good sources for a wide range of may not be associated with antioxidant activity. bioflavonoids, with the ability of reducing inflammation by inhibit- At the present study, we tried to not only explain inflammation, ing cyclooxygenase and lipoxygenase pathways ( Heim et al. 2002 ). disease and its treatments with concentration on medical plants but Flavonoids, are one of the important members in anti-inflammatory collected a sufficient collection of anti-inflammatory plants with fo- components category, with a large family of compounds which repre- cusing on their mechanism of action. But as far as the huge number sent varied biological properties and having the ability of suppressing of existent herbs around the world collecting all together seems to be the expression of inflammatory proteins and cytokines ( Hu and Kitts impossible. 2003; Kim et al. 2004 ). Flavanoieds have been used in the form of crude plant extracts for their anti-inflammatory effects. For example, Conflict of interest it has been confirmed that flavonoids are the major bioactive flavones in Radix Scutellariae (the root of Scutellariae baicalensis Georgi.), The authors declare that there is not any conflict of interest. existing in the forms of aglycones (baicalein, wogonin, oroxylin A) References and glycosides, which are used for the treatment of inflammatory diseases. Abad-Martinez, M.J., Latourrette Bessa, A., Bermejo, B.P., 2005. Biologically active sub- Luteolin, 3 ,4 -dihydroxyflavone, galangin, morin and apigenin stances from the genus Baccharis L. (Compositae). Studies in natural products as some examples of flavonoieds are proven to be inhibitors of chemistry. Bioactive Nat. Prod. 30, 703–760 .

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